The neuroleptic malignant syndrome (NMS) is similar to anesthesia-induced malignant hyperthermia (MH) in three major clinical features: hyperthermia, muscular rigidity, and myoglobinuria. In eight cases of NMS, we studied caffeine contracture of single skinned muscle fibers. Sensitivity of the sarcoplasmic reticulum to caffeine was abnormally increased in six of the eight cases. Morphologic studies showed type 2B fiber atrophy in all six cases examined, and there were necrotic fibers in two cases. Since skeletal muscle is affected in NMS, these patients may be susceptible to MH.